1.
Hsp70 alters tau function and aggregation in an isoform specific manner.
Abstract
Tauopathies are characterized by abnormal aggregation of the microtubule associated protein tau. This aggregation is thought to occur when tau undergoes shifts from its native conformation to one that exposes hydrophobic areas on separate monomers, allowing contact and subsequent association into oligomers and filaments. Molecular chaperones normally function by binding to exposed hydrophobic stretches on proteins and assisting in their refolding. Chaperones of the heat shock protein 70 (Hsp70) family have been implicated in the prevention of abnormal tau aggregation in adult neurons. Tau exists as six alternatively spliced isoforms, and all six isoforms appear capable of forming the pathological aggregates seen in Alzheimer's disease. Because tau isoforms differ in primary sequence, we sought to determine whether Hsp70 would differentially affect the aggregation and microtubule assembly characteristics of the various tauisoforms. We found that Hsp70 inhibits tau aggregation directly, and not through inducer mediated effects. We also determined that Hsp70 inhibits the aggregation of each individual tau isoform and was more effective at inhibiting the three repeat isoforms. . Finally, all tau isoforms robustly induced microtubule formation while in the presence of Hsp70. The results presented herein indicate that Hsp70 affects tau isoform dysfunction while having very little impact on the normal function of tau to mediate microtubule assembly. This indicates that targeting Hsp70 to tau may provide a therapeutic approach for the treatment of tauopathies that avoids disruption of normal tau function.
γ-aminobutyric acid type A (GABAA) receptor activation modulates Tauphosphorylation.
Source
University of Helsinki, Finland.
Abstract
Abnormal phosphorylation and aggregation of the microtubule-associated protein Tau are hallmarks of various neurodegenerative diseases, such as Alzheimer's disease (AD). Molecular mechanisms that regulate Tauphosphorylation are complex and currently incompletely understood. We have developed a novel live-cell reporter system based on protein-fragment complementation assay (PCA) to study dynamic changes in Tau phosphorylation status. In this assay, fusion proteins of Tau and peptidyl-prolyl cis-trans isomerase 1 (Pin1) carrying complementary fragments of a luciferase protein serve as a sensor of altered protein-protein interaction between Tau and Pin1, a critical regulator of Tau dephosphorylation at several disease-associated proline-directed phosphorylation sites. Using this system, we identified several structurally distinct GABA(A) receptor modulators as novel regulators of Tauphosphorylation in a chemical library screen. GABA(A) receptor activation promoted specific phosphorylation of Tau at the AT8 epitope (Ser199/Ser202/Thr205) in cultures of mature cortical neurons. Increased Tau phosphorylation by GABA(A) receptor activity was associated with reduced Tau binding to protein phosphatase 2A and was dependent on Cdk5 but not GSK3β kinase activity.
Amyloid-β Protein Precursor Regulates Phosphorylation and Cellular Compartmentalization of Microtubule Associated Protein Tau.
Source
Dipartimento di Oncologia, Biologia e Genetica, Università degli Studi di Genova, Genova, Italy.
Abstract
Tau is a multifunctional protein detected in different cellular compartments in neuronal and non-neuronal cells. When hyperphosphorylated and aggregated in atrophic neurons, tau is considered the culprit for neuronal death in familial and sporadic tauopathies. With regards to Alzheimer's disease (AD) pathogenesis, it is not yet established whether entangled tau represents a cause or a consequence of neurodegeneration. In fact, it is unquestionably accepted that amyloid-β protein precursor (AβPP) plays a pivotal role in the genesis of the disease, and it is postulated that the formation of toxic amyloid-β peptides from AβPP is the primary event that subsequently induces abnormal tauphosphorylation. In this work, we show that in the brain of AD patients there is an imbalance between the nuclear and the cytoskeletal pools of phospho-tau. We observed that in non-AD subjects, there is a stable pool of phospho-tauwhich remains strictly confined to neuronal nuclei, while nuclear localization of phospho-tau is significantly underrepresented in neurons of AD patients bearing neurofibrillary tangles. A specific phosphorylation of tau is required during mitosis in vitro and in vivo, likely via a Grb2-ERK1/2 signaling cascade. In differentiated neuronal A1 cells, the overexpression of AβPP modulates tau phosphorylation, altering the ratio between cytoskeletal and nuclear pools, and correlates with cell death. Altogether our data provide evidence that AβPP, in addition to amyloid formation, modulates the phosphorylation of tau and its subcellular compartmentalization, an event that may lead to the formation of neurofibrillary tangles and to neurodegeneration when occurring in postmitotic neurons.
Tau protein is involved in morphological plasticity in hippocampal neurons in response to BDNF.
Source
Key Laboratory of Medical Protection for Electromagnetic Radiation Ministry of Education, Department of Occupational Health, Third Military Medical University, Chongqing 400038, China.
Abstract
Tau protein, a microtubule-associated protein involved in a number of neurological disorders such as Alzheimer's disease (AD), may undergo modifications under both physiological and pathological conditions. However, the signaling pathways that couple tau protein to neuronal physiology such as synaptic plasticity have not yet been elucidated. Here we report that tau protein is involved in morphological plasticity in response to brain derived neurotrophic factor (BDNF). Stimulation of the cultured rat hippocampal neurons with BDNF resulted in increased tau protein expression, as detected by Western blotting. Furthermore, tau protein accumulated in the distal region of the neurite when treated with taxol or taxol plus BDNF. The increased tau protein also protected neurons against nocodazole-induced dendrite loss. Moreover, BDNF promoted spine growth as well as tau protein over-expression. Knockdown of tau protein using specific short-hairpin RNA (shRNA) significantly decreased the spine density. And BDNF could not increase the spine density oftau-knockdown neurons. These results highlight a possible role for tau protein in the dynamic rearrangement of cytoskeletal fibers vital for BDNF-induced synaptic plasticity.
Copyright © 2012. Published by Elsevier Ltd.
The tau-like protein in silkworm (Bombyx mori) induces microtubule bundle formation.
Source
The Key Laboratory of Cell Proliferation and Differentiation of Ministry of Education; The State Key Laboratory of Bio-membrane and Membrane Bio-engineering, College of Life Sciences, Peking University, Beijing 100871, China.
Abstract
Tau proteins are major microtubule-associated proteins (MAPs), which promote polymerization of tubulin and determine spacings between microtubules in axons of both the central and peripheral nervous systems (CNS and PNS). Here, we cloned and identified a tau-like protein BmTau from silkworm, Bombyx mori (GenBank accession number FJ904935). The coding sequence of BmTau is 723 bases long and encodes an approximate 30kDa protein. In the C-terminus of BmTau are contained four predicted microtubule-binding domains, which share strong sequence homology to its ortholog in Drosophila melanoganster. Relative real-time PCR analysis showed ubiquitous expression of BmTau in both neurons and non-neural cells, with its mRNA abundantly expressing in brain but significantly less detected in trachea, fat body, and silkgland. Furthermore, immunocytochemical studies in BmN cells transfected with EGFP-BmTau indicated that BmTau functioned as microtubule bundling protein as its orthologues.
- PMID:
- 22201930
- [PubMed - in process]
WW domain-containing oxidoreductase promotes neuronal differentiation via negative regulation of glycogen synthase kinase 3β
Source
Institute of Clinical Medicine, National Cheng Kung University Medical College, Tainan, Taiwan.
Abstract
WW domain-containing oxidoreductase (WWOX), a putative tumour suppressor, is suggested to be involved in the hyperphosphorylation of Alzheimer's Tau. Tau is a microtubule-associated protein that has an important role inmicrotubule assembly and stability. Glycogen synthase kinase 3β (GSK3β) has a vital role in Tau hyperphosphorylation at its microtubule-binding domains. Hyperphosphorylated Tau has a low affinity for microtubules, thus disruptingmicrotubule stability. Bioinformatics analysis indicated that WWOX contains two potential GSK3β-binding FXXXLI/VXRLE motifs. Immunofluorescence, immunoprecipitation and molecular modelling showed that WWOX interacts physically with GSK3β. We demonstrated biochemically that WWOX can bind directly to GSK3β through its short-chain alcohol dehydrogenase/reductase domain. Moreover, the overexpression of WWOX inhibited GSK3β-stimulated S396 and S404 phosphorylation within the microtubule domains of Tau, indicating that WWOX is involved in regulating GSK3β activity in cells. WWOX repressed GSK3β activity, restored the microtubule assembly activity of Tau and promoted neurite outgrowth in SH-SY5Y cells. Conversely, RNAi-mediated knockdown of WWOX in retinoic acid (RA)-differentiated SH-SY5Y cells inhibited neurite outgrowth. These results suggest that WWOX is likely to be involved in regulating GSK3β activity, reducing the level of phosphorylated Tau, and subsequently promoting neurite outgrowth during neuron differentiation. In summary, our data reveal a novel mechanism by which WWOX promotes neuronal differentiation in response to RA.Cell Death and Differentiation advance online publication, 23 December 2011; doi:10.1038/cdd.2011.188.
Effect of chronic administration of estradiol, progesterone, and tibolone on the expression and phosphorylation of glycogen synthase kinase-3β and themicrotubule-associated protein tau in the hippocampus and cerebellum of female rat.
Source
Unidad de Investigación Médica en Farmacología, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México D.F., México.
Abstract
Gonadal hormones regulate expression and activation of protein tau. Tibolone is a drug used as first- choice comprehensive treatment for the relief of menopausal symptoms, because it and its various metabolites have estrogenic properties and progestogenic/androgenic effects; however, the effect on the activation of tau protein and its signaling cascade in the brain is unknown. We studied the effect of chronic administration of estradiol (E2), progesterone (P4), and tibolone (TIB) on the expression and phosphorylation of microtubule-associated protein tau and glycogen synthase kinase-3β (GSK3β) in the hippocampus and cerebellum of ovariectomized rats. Ovariectomized adult female rats were implanted with pellets of vehicle, E2, or P4 or were treated with TIB by oral administration for 60 days. The animals were sacrificed, and tissue proteins were analyzed by Western blot. We observed that, in the hippocampus, administration of E2, P4, or TIB significantly decreased the protein content of hyperphosphorylated tau and increased the taudephosphorylated form, whereas only treatment with TIB increased the content of the phosphorylated form of GSK3β. In the cerebellum, E2 and TIB treatments resulted in a significant decrease in the expression of hyperphosphorylated tau, whereas E2 and TIB increased phosphorylated GSK3β; P4 had no effect. These results indicate that chronic administration of gonadal hormones and tibolone modulates tau and GSK3β phosphorylation in hippocampus and cerebellum of the rat and may exert a neuroprotective effect in these tissues. © 2011 Wiley Periodicals, Inc.
Copyright © 2011 Wiley Periodicals, Inc.
Frontotemporal lobar degeneration-related proteins induce only subtle memory-related deficits when bilaterally overexpressed in the dorsal hippocampus.
Source
Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, 1501 Kings Hwy, Shreveport, LA 71130, USA.
Abstract
Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disease that involves cognitive decline and dementia. To model the hippocampal neurodegeneration and memory-related behavioral impairment that occurs in FTLD and othertau and TDP-43 proteinopathy diseases, we used an adeno-associated virus serotype 9 (AAV9) vector to induce bilateral expression of either microtubule-associated protein tau or transactive response DNA binding protein 43kDa (TDP-43) in adult rat dorsal hippocampus. Human wild-type forms of tau or TDP-43 were expressed. The vectors/doses were designed for moderate expression levels within neurons. Rats were evaluated for acquisition and retention in the Morris water task over 12weeks after gene transfer. Neither vector altered acquisition performance compared to controls. In measurements of retention, there was impairment in the TDP-43 group. Histological examination revealed specific loss of dentate gyrus granule cells and concomitant gliosis proximal to the injection site in the TDP-43 group, with shrinkage of the dorsal hippocampus. Despite specific tau pathology, the tau gene transfer surprisingly did not cause obvious neuronal loss or behavioral impairment. The data demonstrate that TDP-43 produced mild behavioral impairment and hippocampal neurodegeneration in rats, whereas tau did not. The models could be of value for studying mechanisms of FTLD and other diseases with tau and TDP-43 pathology in the hippocampus including Alzheimer's disease, with relevance to early stage mild impairment.
Copyright © 2011 Elsevier Inc. All rights reserved.
Tau-Targeted Immunization Impedes Progression of Neurofibrillary Histopathology in Aged P301L Tau Transgenic Mice.
Source
Laboratory for Translational Neurodegeneration, Brain and Mind Research Institute, The University of Sydney, Camperdown, New South Wales, Australia.
Abstract
In Alzheimer's disease (AD) brains, the microtubule-associated protein tau and amyloid-β (Aβ) deposit as intracellular neurofibrillary tangles (NFTs) and extracellular plaques, respectively. Tau deposits are furthermore found in a significant number of frontotemporal dementia cases. These diseases are characterized by progressive neurodegeneration, the loss of intellectual capabilities and behavioral changes. Unfortunately, the currently available therapies are limited to symptomatic relief. While active immunization against Aβ has shown efficacy in both various AD mouse models and patients with AD, immunization against pathogenic tau has only recently been shown to prevent pathology in young tautransgenic mice. However, if translated to humans, diagnosis and treatment would be routinely done when symptoms are overt, meaning that the histopathological changes have already progressed. Therefore, we used active immunization to target pathogenic tau in 4, 8, and 18 months-old P301L tau transgenic pR5 mice that have an onset of NFT pathology at 6 months of age. In all age groups, NFT pathology was significantly reduced in treated compared to control pR5 mice. Similarly, phosphorylation of tau at pathological sites was reduced. In addition, increased astrocytosis was found in the oldest treated group. Taken together, our data suggests that tau-targeted immunization slows the progression of NFT pathology in mice, with practical implications for human patients.
Hyperphosphorylated tau in young and middle-aged subjects.
Source
Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University/Uppsala University Hospital, Dag Hammarskjölds väg 20, 751 85, Uppsala, Sweden.
Abstract
The brain tissue obtained from ninety-five cognitively unimpaired subjects, with ages ranging from 22 to 50 years upon death, were immunohistochemically assessed for neurodegenerative changes, i.e., hyperphosphorylated tau (HPτ) and β-amyloid (Aβ) pathology in predilection neuroanatomical areas. HPτ pathology was observed in the transentorhinal cortex and/or the locus coeruleus (LC) in 33% of the subjects, without any obvious risk factors known to alter themicrotubule-associated protein. HPτ pathology was noted in the LC in 25 out of 83 subjects (30%), lacking concomitant cortical Aβ or transentorhinal HPτ pathology. This observation was present even when assessing only one routine section of 7 μm thickness. The recent suggestion of prion-like propagation of neurodegeneration and the finding of neurodegeneration being quite common in middle-aged persons is alarming. It is noteworthy, however, that a substantial number of neurologically unimpaired subjects even at a very old age display only sparse to modest extent of neurodegenerative pathology. Thus, only a subset of subjects with neurodegenerative changes early in life seem to progress to a symptomatic disease with ageing. This observation brings forth the notion that other, yet unknown modifying factors influence the progression of degeneration that leads to a symptomatic disorder. The known association between alterations in the LC and mood disorders, and the finding of the LC being frequently affected with HPτ pathology suggest that clinicopathological studies on young subjects both with or without mood disorders are warranted.
Linking Amyloid-β and Tau: Amyloid-β Induced Synaptic Dysfunction via Local Wreckage of the Neuronal Cytoskeleton.
Source
Max Planck Unit for Structural Molecular Biology, Hamburg, Germany.
Abstract
Background: In Alzheimer's disease (AD), amyloid-β (Aβ) is the major component of extracellular plaques, whereas themicrotubule-associated protein tau forms the main component of intracellular tangles. In contrast to frontotemporal dementias and other neurodegenerative diseases, both proteins form pathological aggregates and are considered key players for the development of AD. However, the connection between Aβ and tau and the functional loss of neurons and synapses, which ultimately lead to cognitive impairments, is still not well understood. Objectives: Making use of primary neurons exposed to Aβ oligomers, we sought to determine how tau mediates the Aβ-induced neuronal dysfunction. Additionally, we asked how the microtubule cytoskeleton is involved in the combined Aβ and tau toxicity. Methods: We exposed mature primary rat neurons with developed synapses to Aβ oligomers and used immunofluorescence and electron microscopy to investigate tau, actin, neurofilament and microtuble cytoskeleton changes. Results: Aβ oligomers preferentially associate with synapses, notably dendritic spines, throughout the neuronal cell culture. As a consequence, endogenous tau gets missorted from the axonal into the somatodendritic compartment in a subset of cells. These missorted cells also display missorting of neurofilaments, and a dramatic loss of microtubules, which can be prevented by the microtubule stabilizer taxol. Conclusions: Aβ causes tau missorting, loss of neuronal cell polarity and loss of dendritic microtubules. This in turn leads to impaired organelle/mitochondria transport, whereby synapses cannot be maintained properly and eventually decay. The data support the view that the microtubule cytoskeleton is a valid therapeutic target in AD.
Copyright © 2011 S. Karger AG, Basel.
Enriched odor exposure decrease tau phosphorylation in the rat hippocampus and cortex.
Source
Department of Pathophysiology, Key Laboratory of Neurological Diseases of Education Committee of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
Abstract
Abnormally hyperphosphorylated microtubule-associated protein tau is the main component of the neurofibrillary tangles (NFT), a hallmark pathological feature of Alzheimer's disease (AD). A lot of studies suggested that there is highly neurobiological correlation between olfactory dysfunction and AD-like pathology, but the effect of the odor stimulation ontau phosphorylation remains unknown. Here, we examined the effect of short-term and long-term enriched odor exposure on the alterations of tau phosphorylation at multiple sites in the rat brains. We found that short-term odor enrichment did not affect the phosphorylation of tau, while long-term odor enrichment dramatically reduce the phosphorylation level oftau at Ser198/199/202, Thr231, Ser396, and Ser404 sites both in the hippocampus and cortex. These data suggest that long-term odor exposure prevent tau phosphorylation and may be a new therapeutic strategy of AD.
Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Prevalence of frontotemporal lobar degeneration in an isolated population: the Vallecamonica study.
Source
Department of Neurology, University of Brescia, Brescia, Italy.
Abstract
The study of neurodegenerative diseases, such as frontotemporal lobar degeneration (FTLD), in isolated populations represents a privileged point of view for identifying new causative genes and pathogenetic mechanisms. Vallecamonica is a valley located in the Brescia province (Northern Italy), which experienced isolation until the end of World War II. The aims of the present work were (1) to estimate the prevalence of FTLD in Vallecamonica, (2) to determine the monogenic FTLD forms, and (3) to identify FTLD cases with no evidence of known pathogenetic mutations and the related clinical features. Patients meeting current clinical criteria for FTLD were considered. Mutation analysis for microtubule associated protein tau (MAPT) and progranulin (PGRN) genes was performed, as well as serum PGRN dosage. On the census day, 42 FTLD patients were alive, resulting in an overall disease prevalence of 35 per 100 inhabitants. Thirty-one out of 42 patients underwent sequencing analysis. Five patients carried PGRN Thr272fs mutation and one patient MAPT P301L mutation. There were no differences in term of age at onset and gender between this group and mutation carriers, but the latter had greater family history for dementia (100%, P = 0.01). In Vallecamonica, we detected a higher prevalence of FTLD compared with that already reported in other populations. A founder effect or a genetic drift might be considered for an allelic enrichment. Ongoing study aims to identify the presence of a new genetic form in those FTLD patients without known pathogenetic mutations in this isolated population.
[108th Scientific Meeting of the Japanese Society of Internal Medicine: symposium: 1. Progress in dementia research--dementia disorders andprotein; (4) Tau protein: mechanism and classification of the diseases].
Source
Department of Neurology, Juntendo University and Juntendo Koshigaya Hospital, Japan.
- PMID:
- 22117338
- [PubMed - indexed for MEDLINE]
Alzheimer disease biomarkers are associated with body mass index.
Source
Department of Neurology, University of Kansas School of Medicine, Kansas City, KS 66160, USA.
Abstract
OBJECTIVE:
Both low and high body mass index (BMI) has been associated with cognitive impairment and dementia risk, including Alzheimer disease (AD). We examined the relationship of BMI with potential underlying biological substrates for cognitive impairment.
METHODS:
We analyzed cross-sectional data from participants enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) with PET imaging using Pittsburgh Compound B (PiB, n = 101) or CSF analyses (n = 405) for β-amyloid peptide (Aβ) and total tau. We assessed the relationship of CSF biomarkers and global PiB uptake with BMI using linear regression controlling for age and sex. We also assessed BMI differences between those who were and were not considered biomarker positive. Finally, we assessed BMI change over 2 years in relationship to AD biomarkers.
RESULTS:
No dementia, mild cognitive impairment (MCI), and AD groups were not different in age, education, or BMI. In the overall sample, CSF Aβ (β = 0.181, p < 0.001), tau (β = -0.179, p < 0.001), tau/Aβ ratio (β = -0.180, p < 0.001), and global PiB uptake (β = -0.272, p = 0.005) were associated with BMI, with markers of increased AD burden associatedwith lower BMI. Fewer overweight individuals had biomarker levels indicative of pathophysiology (p < 0.01). These relationships were strongest in the MCI and no dementia groups.
CONCLUSIONS:
The presence and burden of in vivo biomarkers of cerebral amyloid and tau are associated with lower BMI in cognitively normal and MCI individuals. This supports previous findings of systemic change in the earliest phases of the disease. Further, MCI in those who are overweight may be more likely to result from heterogeneous pathophysiology.
- PMID:
- 22105948
- [PubMed - indexed for MEDLINE]
- PMCID: PMC3233188
- [Available on 2012/11/22]
SNCA and MAPT genes: Independent and joint effects in Parkinson disease in the Italian population.
Source
Dipartimento di Biologia e Genetica per le Scienze Mediche, Università degli Studi di Milano, Milan, Italy; Medical Genetics Laboratory, Foundation IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.
Abstract
BACKGROUND:
Significant efforts have been focused on investigating the contribution of common variants to Parkinson disease (PD) risk. Several independent GWAS and metanalysis studies have shown a genome-wide significant association of single nucleotide polymorphisms (SNPs) in the α-synuclein (SNCA) and microtubule-associated proteintau (MAPT) regions. Here we investigated the role of SNCA and MAPT as PD susceptibility genes in a large Italian population of 904 patients and 891 controls. An evaluation of gene-gene and gene-environment interactions in association with PD was also attempted.
METHODS:
The SNCA Rep1 microsatellite was genotyped by a fluorescent PCR assay, whereas the SNPlex genotyping system was used to genotype 12 additional markers across the SNCA gene, and 2 SNPs tagging the risk MAPT H1 haplotype.
RESULTS:
Single-marker analysis demonstrated nominal evidence of association for: i) the 261-bp-long allele of Rep1; ii) 7 SNPs in the SNCA region (top SNP: rs356186, P = 3.08 × 10(-04), intron 4); iii) both SNPs identifying the MAPT H1 haplotype (P = 4.63 × 10(-04) and P = 4.23 × 10(-04) for rs1800547 and rs9468, respectively). Moreover, we found a highly significant protective haplotype spanning ∼83 kb from intron 4 to the 3' end of SNCA (P = 1.29 × 10(-05)).
CONCLUSIONS:
Our findings strongly confirm SNCA and MAPT as major PD susceptibility genes for idiopathic PD in the Italian population. Interaction analyses did not evidence either epistatic effects between the two loci or gene-environment interactions.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Insight into Potential Cu(II)-Binding Motifs in the Four Pseudorepeats of TauProtein.
Source
Department of Chemistry, University of Pittsburgh , 219 Parkman Avenue, Pittsburgh, Pennsylvania 15260, United States.
Abstract
Tau protein and Cu(II) are believed to be associated with the pathogenesis of Alzheimer's disease. However, little is known about atomic-level interactions between tau protein and Cu(II). Herein, we suggest, on the basis of electron spin resonance (ESR) data, that the four pseudorepeats of tau protein in the microtubule-binding region play an important role in Cu(II) binding. We use a number of tau protein fragments in order to examine Cu(II)-binding site(s) and binding affinities. Continuous-wave (CW) ESR experiments on the four highly conserved octadecapeptides, each of which is a segment of one of the four pseudorepeats, reveal that the equimolar Cu(II) complexes of the four octadecapeptides are similar to one another in terms of the coordination environment and binding affinity. The spectra obtained with pulsed ESR techniques such as electron spin-echo envelope modulation and hyperfine sublevel correlation provide direct evidence that a histidine residue and a backbone amide group coordinate to Cu(II) in each Cu(II)-octadecapeptide complex. The results of CW and pulsed ESR experiments on some chemically modified peptides indicate that the cysteine residues in the second and third pseudorepeats are unlikely to be involved in Cu(II) binding. On the other hand, similar experiments on tau fragments of the second pseudorepeat with different lengths lead to the conclusion that the affinity for Cu(II) decreases as the octadecapeptide is either truncated or elongated. The high Cu(II)-binding affinity of the octadecapeptide is presumably due to the N-terminal amino group stabilizing the Cu(II)-octadecapeptide complex. Finally, the ESR data for a longer tau fragment that contains two octadecapeptides suggest that the Cu(II) binding site(s) of even longer fragments of tau protein is similar to that of a single octadecapeptide.
Neurological biomarkers in the perioperative period.
Source
Department of Anaesthesiology and Perioperative Medicine, The University of Texas-MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. jcata@mdanderson.org
Abstract
The rapid detection and evaluation of patients presenting with perioperative neurological dysfunction is of great clinical relevance. Biomarkers have been defined as biological molecules that can be used as an indicator of new onset or progression of a biological process or effect of treatment. Biomarkers have become increasingly important in this setting to supplement other modalities of diagnosis such as EEG, sensory- or motor-evoked potential, transcranial Doppler, near-infrared spectroscopy, or imaging methods. A number of neuro-proteins have been identified and are currently under investigation for potential to provide insights into injury severity, outcome, and the ability to monitor cellular damage and molecular events that occur during neurological injury. S100B is a protein released by glial cells and is considered a marker of blood-brain barrier dysfunction. Clinical studies in patients undergoing cardiac and non-cardiac surgery indicate that serum levels of S100B are increased intraoperatively and after operation. The neurone-specific enolase has also been extensively investigated as a potential marker of neuronal injury in the context of cardiac and non-cardiac surgery. A third biomarker of interest is the Tau protein, which has been linked to neurodegenerative disorders. Tauappears to be more specific than the previous two biomarkers since it is only found in the central nervous system. The metalloproteinase and ubiquitin C terminal hydroxylase-L1 (UCH-L1) are the most recently researched markers; however, their usefulness is still unclear. This review presents a comprehensive overview of S100B, neuronal-specific enolase, metalloproteinases, and UCH-L1 in the perioperative period.
Protein binding in patients with late-life depression.
Source
Department of Psychiatry, University of Illinois at Chicago, USA. akumar@psych.uic.edu
Abstract
CONTEXT:
Depression has been identified as a risk factor and a prodrome of dementia. Common neurobiological mechanisms may underlie this clinical and phenomenologic overlap.
OBJECTIVE:
To examine and compare protein (amyloid and tau) binding in critical brain regions in patients diagnosed as having late-life major depressive disorder (MDD) and healthy control individuals using 2-(1-{6-[(2-[(18)F]fluoroethyl)(methyl)-amino]-2-naphthyl}ethylidene) malononitrile ([(18)F]FDDNP) positron emission tomography.
DESIGN:
A cross-section neuroimaging study using positron emission tomography.
SETTING:
University of California, Los Angeles. Patients Our samples comprised 20 patients diagnosed as having MDD and 19 healthy control individuals of comparable age, sex, and educational level. Main Outcome Measure Relative distribution volume in regions of interest was used as the measure of [(18)F]FDDNP binding in all study participants.
RESULTS:
When compared with controls, [(18)F]FDDNP binding was significantly higher overall and in the posterior cingulate and lateral temporal regions in the MDD group.
CONCLUSIONS:
These findings suggest that neuronal injury associated with higher protein load in critical brain regions might provide a mechanism in the pathophysiologic manifestation of MDD in late life and have implications for the therapeutics of depression in elderly individuals.
PTEN, tau-AP-3, thymidylate synthase immunohistochemistry scoring expression in patients with uterine leiomyomas, uterine smooth muscle tumors of uncertain malignancy potential and uterine leiomyosarcomas.
Source
Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, Taiwan.
Abstract
Uterine smooth muscle tumors are frequently classified as benign and malignant. However, an assortment of mitotic counts and nuclear atypia can be indecisive between uncertain malignant potential, and malignant uterine smooth muscle tumors. We applied three immunohistochemical parameters to distinguish between cases of benign, malignant, and those with uncertain malignant histology.
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